Artificial Sweeteners and Obesity: More than an Association?

Kristina I. Rother, MD, MHSc

Chief, Section on Pediatric Diabetes and Endocrinology Diabetes, Endocrinology, and Obesity Branch

NIDDK

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Disclosure: No conflicts of interest

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Artificial Sweeteners and Obesity

Outline 1) Brief overview of commonly used artificial

sweeteners and how they convey sweetness

2) Studies reporting an association between artificial sweetener use and obesity

3) Data & concepts refuting or supporting a causal role

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Aspartic Acid Phenylalanine Methanol

Saccharin 300x

ADI ~ 3 sodas

Aspartame 200x

ADI ~ 18 sodas

Acesulfame-K 200x

ADI ~ 30 sodas

Sucralose 600x

ADI ~ 6 sodas

Sucrose

FDA Regulates 6 Artificial Sweeteners

Neotame & Advantame 10,000-20,000x ADI ~ 30 sodas

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Aspartic Acid Phenylalanine Methanol

Saccharin ADI ~ 3 sodas

Aspartame ADI ~ 18 sodas

Acesulfame-K ADI ~ 30 sodas

Sucralose ADI ~ 5 sodas

FDA Regulates 6 Artificial Sweeteners

Neotame ADI ~ 30 sodas

Accepted Daily Intake (ADI) 5 mg/kg

Sucrose

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Aspartic Acid Phenylalanine Methanol

Saccharin ADI ~ 3 sodas

Aspartame ADI ~ 18 sodas

Acesulfame-K ADI ~ 30 sodas

Sucralose ADI ~ 5 sodas

Stevia (and sugar alcohols) not included in this presentation

Neotame ADI ~ 30 sodas

5 mg/kg

Rebaudioside A

300x

ADI ~ 3 sodas

Sucrose

Saccharin

Saccharin

Constantine Fahlberg Ira Remsen

Saccharin

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Saccharin

Constantine Fahlberg Ira Remsen

Johns Hopkins University in 1877

Saccharin

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Saccharin

Constantine Fahlberg Ira Remsen Russian сахар (sakar) Latin succarum German Zucker Arabic ُسّكر(súkkar) Persian شکر (šakar) Sanskrit शर्क रा (śárkarā)

Saccharin

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How do artificial sweeteners work? How Non-Nutritive Sweeteners Signal

Chandrashekar et. al., Nature, 2006 10

Taste Bud

Taste Papillae

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How do artificial sweeteners work? How Non-Nutritive Sweeteners Signal

Chandrashekar et. al., Nature, 2006 11

Taste Bud

Taste Papillae

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How do artificial sweeteners work? How Non-Nutritive Sweeteners Signal

Chandrashekar et. al., Nature, 2006 12

Taste Bud

Taste Papillae

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How do artificial sweeteners work? How Non-Nutritive Sweeteners Signal

Chandrashekar et. al., Nature, 2006 13

Taste Bud

Taste Papillae

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Taste Receptor Expression

Ehrenberg R,

ScienceNews 2010, Vol 177

Glucose or artificial sweeteners SGLT-1 GLUT2

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Taste Receptor Expression

Ehrenberg R,

ScienceNews 2010, Vol 177

GLP1

Intestine

Glucose or artificial sweeteners SGLT-1 GLUT2

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Taste Receptor Expression

Ehrenberg R,

ScienceNews 2010, Vol 177

GLP1 Glucagon Like Peptide 1 (GLP1)

Gastric Emptying

Appetite

Glucagon

Insulin

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Artificial Sweeteners and Obesity

Outline 1) Brief overview of commonly used artificial

sweeteners and how they convey sweetness

2) Studies reporting an association between artificial sweetener use and obesity

3) Data & concepts refuting or supporting a causal role

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26.9 %

*Sylvetsky AC et al. Am J Clin Nutr 2012

10%

40%

30%

20%

% P

op

ula

tio

n

Obesity and Artificial Sweetener Use

Secular Trend between1960 and 2010

% obese (BMI > 30 kg/m2)

2011-12

34.9 % JAMA – Feb 2014

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26.9 %

% obese (BMI > 30 kg/m2)

% consuming artificial sweeteners

*Sylvetsky AC et al. Am J Clin Nutr 2012

10%

40%

30%

20%

% Population

32.0 %*

Obesity and Artificial Sweetener Use

34.9 %

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Fueling the Obesity Epidemic? Artificially Sweetened Beverage Use and

Long-term Weight Gain

San Antonio Heart Study

Change of BMI after 7-8 yr follow-up according to diet soda consumption

Sharon P. Fowler, et al. Obesity (2008)

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Obesity and Artificial Sweetener Use

Example

Sharon P. Fowler, et al. Obesity (2008)

Change of BMI after 7-8 yr follow-up according to diet soda consumption

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Female 5’6”, 155 lb, BMI 25.0

1 diet soda a day 165 lb, BMI 26.5

161 lb, BMI 26.0

7-8 years later…………

Obesity and Artificial Sweetener Use

Sharon P. Fowler, et al. Obesity (2008)

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Artificial Sweeteners and Obesity

Outline 1) Brief overview of commonly used artificial

sweeteners and how they convey sweetness

2) Studies reporting an association between artificial sweetener use and obesity

3) Data & concepts refuting or supporting a causal role

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Artificial Sweeteners and Obesity

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Artificial Sweeteners and Obesity

Ace-K , Saccharin & Sucralose 3T3-L1 cells: Adipogenesis Mature adipocytes: Lipolysis hMSCs: Lipolysis** Simon BR, et al. JBC 2013 **Sen (unpublished)

Sucralose and Saccharin MIN6 cells & primary rodent pancreatic beta-cells: Insulin secretion Nakagava Y, et al, PLoS One 2009 Corkey, Diabetes 2012

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Artificial Sweeteners and Obesity

Sucralose > Aspartame > Saccharin bacteriostatic

Abou Donia, et al 2008 (Splenda)

Schiffman, Rother. J Toxicol Environ Health B Crit Rev. 2013

Suppression of intestinal microflora

Prashant GM, et al. Contemp Dent Pract 2012

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Questions

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Questions

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Questions

381 non-diabetic individuals (44% male, age 43.3 yr)

N=40

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Artificial Sweeteners and Obesity

Acesulfame-K Lactating rats concentrate Ace-K 6-fold in breast milk (IPCS Inchem 0.7967)

Our preliminary data Higher Ace-K concentrations in human breast milk than in serum Also frequently detectable: saccharin, sucralose

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Artificial Sweeteners and Obesity

Offspring exposed during pregnancy or lactation had higher preferences for sweetness, whether non-caloric (ace-K) or caloric (sucrose) compared to control animals

Clinical Implication?

Not studied in humans – yet……….

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Artificial Sweeteners and Obesity

Which artificial sweetener(s)? In which context? In which cohort?

Randomized, acute interventions studies in humans

Artificial Sweeteners and Obesity

Method: Diet soda (Diet RiteTM with ace-K & sucralose) vs. carbonated water before OGTT

Subjects: 12-25 years

Brown RJ, Walter M, Rother KI. Diabetes Care 2009 and 2012

or

OGTT

AUC 34% higher (p = 0.029)

AUC 43% higher (p = 0.020)

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GLP-1 in Healthy Volunteers (n=22) GLP-1 in Type 1 Diabetes (n=11)

Glucose or artificial sweeteners SGLT-1 GLUT2

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Taste Receptor Expression

Ehrenberg R, ScienceNews 2010, Vol 177

GLP1 Glucagon Like Peptide 1 (GLP1)

Gastric Emptying

Appetite

Glucagon

Insulin

Neutraceuticals

Glutamine

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Artificial Sweeteners and Obesity

Glucose incremental peak (p=0.03) Insulin AUC p=0.03 Insulin incremental peak p=0.06

Sucralose affects glycemic and hormonal responses to an OGTT. Pepino MY, Tiemann CD, Patterson BW, Wice BM, Klein S.

Diabetes Care 2013

N=17, BMI 42 kg/m2

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Artificial Sweeteners and Obesity

Glucose incremental peak (p=0.03) Insulin AUC p=0.03 Insulin incremental peak p=0.06

31 healthy adult volunteers (BMI 26 kg/m2)

Our own data:

AUC (sweetener pre-treatment) – AUC (water pretreatment)

RESULTS

or

Prior to OGTT

Artificial Sweeteners and Obesity

31 healthy adult volunteers

Our own (unpublished) data

or

Prior to OGTT

Artificial Sweeteners and Obesity

Beyond acute sweetener exposure, what do long-term studies show?

Artificial Sweeteners and Obesity

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N Engl J Med. 2012 Oct 11

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• Overweight & obese adolescents (n=224) who habitually consumed SSB randomized to:

• Home delivery of non-caloric drinks (intervention) or • Supermarket gift cards but no instructions of what to

purchase (control)

• Intervention lasted 1 year with 1 additional year follow-up

• Result: less weight gain after 1st year, no difference after 2nd year

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• Elementary school children (n=641) who habitually consumed sugar sweetened beverages randomized to:

• 1 can (8 oz.) of 0 kcal artificially sweetened drink

• 1 identical can (8 oz.) of 104 kcal sugar-containing drink

• Drinks were consumed in school (5 days per week) and at home on weekends for 18 months

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If a child stays on the same percentiles for height and weight BMI-z score = 0

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1 kg difference in weight gain after 18 months (p<0.001)

Artificial Sweetener group Sugar groupr

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Caveat: Lack of control group Interpretation: Kids who continue to drink regular soda in school gain more weight.

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Artificial Sweeteners and Obesity

Reward

Food Navigator.com 24-Sep-2013

Key Concept: Reward

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Both sucrose and sucralose activate the bilateral primary taste cortex (frontal operculum, anterior insula) Sucralose (artificial sweetener) did NOT activate anteroventral striatum (AVS), nucleus accumbens and midbrain substantia nigra and ventral tegmental areas

Sucrose

Sweetener (sucralose)

Frank GKW, et al. NeuroImage 2008

fMRI: Sucrose versus Sucralose

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Artificial Sweeteners and Obesity

So far, no convincing evidence that artificial sweeteners prevent or alleviate obesity

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Artificial Sweeteners and Obesity

So far, no convincing evidence that artificial sweeteners prevent or alleviate obesity

IN CONTRAST: More adipogenesis and less lipolysis (in vitro) More insulin secretion (in vitro/in vivo) Less reward (in vivo)

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Thank You

Acknowledgements Allison Sylvetsky, PhD Alexandra Gardner, BA Jenny Blau, MD Rebecca Brown, MD, MHSc Marisa Abegg, BA Tammy Nguyen, BS Mary Walter, PhD Peter Walter, PhD Martin Garraffo, PhD Nursing Staff 5SWS Study Participants

Extramural Collaborators: Claire Fraser, PhD (University of MD) Steven Munger, PhD (University of MD) Susan Schiffman, PhD (NC State University)

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Stevia Made from the leaves of a shrub that grows in South and Central America There are no long-term studies of health effects (but long-term use) Sugar alcohols Examples: Erythritol, xylitol, mannitol, maltitol used for decades to sweeten chewing gum, candy, fruit spreads, toothpaste, cough syrup, and other products. Newer, cheaper technologies (producing sugar alcohols from corn, wood, and other plant materials) explain their increased use.

Harvard School of Public Health Nutrition Source

Non-Nutritive Sweeteners FDA regulated as GRAS

Rebaudioside A

300x

ADI ~ 3 sodas

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Questions

Spearman correlation to NAS consumption

R q

BPSys 0.29 5.0E-08 7.0E-07

BMI 0.28 1.0E-07 7.0E-07

Bpdia 0.26 9.0E-07 4.0E-06

Waist-hip Ratio 0.21 1.0E-04 4.0E-04

HbA1c% 0.20 1.0E-04 4.0E-04

Fasting glucose 0.19 3.0E-04 9.0E-04

Weight 0.17 1.0E-03 3.0E-03

GTT 0.13 1.0E-02 2.0E-02

ALT 0.13 1.0E-02 2.0E-02

381 non-diabetic individuals (44% male, age 43.3 yr)

N=40

Main Learning Objectives Distinguish between different artificial sweeteners Describe their mechanism of action Recognize the difficulties in establishing causality for obesity promoting effects

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7 7 individuals (5 male, age 28-36 yr) get saccharin at max ADI and daily (!!!) OGTTs